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Nogo-B, a ubiquitously expressed member of the reticulon family, plays an important role in maintaining endoplasmic reticulum (ER) structure, regulating protein folding, and calcium homeostasis. In this study, we demonstrate that Nogo-B expression and secretion are upregulated in lung cancer and correlate to overall survival. Nogo-B is secreted by various cells, particularly lung cancer cells. ER stress and phosphorylation at serine 107 can induce Nogo-B secretion. Secretory Nogo-B suppresses the differentiation of Th2 cells and the release of type 2 cytokines, thus influencing the anti-tumor effects of Th2-related immune cells, including IgE+B cell class switching and eosinophil activation.
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Différenciation cellulaire , Tumeurs du poumon , Protéines Nogo , Lymphocytes auxiliaires Th2 , Microenvironnement tumoral , Humains , Tumeurs du poumon/immunologie , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/génétique , Tumeurs du poumon/métabolisme , Microenvironnement tumoral/immunologie , Lymphocytes auxiliaires Th2/immunologie , Protéines Nogo/métabolisme , Protéines Nogo/génétique , Stress du réticulum endoplasmique/immunologie , Lignée cellulaire tumorale , Cytokines/métabolisme , Mâle , Femelle , PhosphorylationRÉSUMÉ
In response to antigens, B cells undergo affinity maturation and class switching mediated by activation-induced cytidine deaminase (AID) in germinal centers (GCs) of secondary lymphoid organs, but uncontrolled AID activity can precipitate autoimmunity and cancer. The regulation of GC antibody diversification is of fundamental importance but not well understood. We found that autoimmune regulator (AIRE), the molecule essential for T cell tolerance, is expressed in GC B cells in a CD40-dependent manner, interacts with AID and negatively regulates antibody affinity maturation and class switching by inhibiting AID function. AIRE deficiency in B cells caused altered antibody repertoire, increased somatic hypermutations, elevated autoantibodies to T helper 17 effector cytokines and defective control of skin Candida albicans. These results define a GC B cell checkpoint of humoral immunity and illuminate new approaches of generating high-affinity neutralizing antibodies for immunotherapy.
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Stress-induced hair loss is a prevalent health concern, with mechanisms that remain unclear, and effective treatment options are not yet available. In this study, we investigated whether stress-induced hair loss was related to an imbalanced immune microenvironment. Screening the skin-infiltrated immune cells in a stressed mouse model, we discovered a significant increase in macrophages upon stress induction. Clearance of macrophages rescues mice from stress-induced hair shedding and depletion of hair follicle stem cells (HFSCs) in the skin, demonstrating the role of macrophages in triggering hair loss in response to stress. Further flow cytometry analysis revealed a significant increase in M1 phenotype macrophages in mice under stressed conditions. In searching for humoral factors mediating stress-induced macrophage polarization, we found that the hormone Norepinephrine (NE) was elevated in the blood of stressed mice. In addition, in-vivo and in-vitro studies confirm that NE can induce macrophage polarization toward M1 through the ß-adrenergic receptor, Adrb2. Transcriptome, enzyme-linked immunosorbent assay (ELISA), and western blot analyses reveal that the NLRP3/caspase-1 inflammasome signaling and its downstream effector interleukin 18 (IL-18) and interleukin 1 beta (IL-1ß) were significantly upregulated in the NE-treated macrophages. However, inhibition of the NE receptor Adrb2 with ICI118551 reversed the upregulation of NLRP3/caspase-1, IL-18, and IL-1ß. Indeed, IL-18 and IL-1ß treatments lead to apoptosis of HFSCs. More importantly, blocking IL-18 and IL-1ß signals reversed HFSCs depletion in skin organoid models and attenuated stress-induced hair shedding in mice. Taken together, this study demonstrates the role of the neural (stress)-endocrine (NE)-immune (M1 macrophages) axis in stress-induced hair shedding and suggestes that IL-18 or IL-1ß may be promising therapeutic targets.
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Alopécie , Interleukine-18 , Interleukine-1 bêta , Protéine-3 de la famille des NLR contenant un domaine pyrine , Stress psychologique , Animaux , Souris , Alopécie/immunologie , Caspases , Inflammasomes , Interleukine-18/génétique , Interleukine-18/pharmacologie , Interleukine-18/usage thérapeutique , Interleukine-1 bêta/génétique , Interleukine-1 bêta/pharmacologie , Interleukine-1 bêta/usage thérapeutique , Macrophages , Protéine-3 de la famille des NLR contenant un domaine pyrine/génétique , Stress psychologique/complications , Norépinéphrine/usage thérapeutique , Agonistes des récepteurs alpha-2 adrénergiques/usage thérapeutique , Apoptose/effets des médicaments et des substances chimiquesRÉSUMÉ
OBJECTIVES: To investigate factors that may influence humoral immunity post-vaccination with a COVID-19-inactivated vaccine (SC2IV). METHODS: A total of 1596 healthy individuals from the Seventh Affiliated Hospital, Sun Yat-sen University (1217) and Shenzhen Baotian Hospital (379) were enrolled in this study among which 694 and 218 participants were vaccinated with two-dose SC2IV, respectively. Physical examination indices were recorded. The levels of neutralizing antibody (NA), Spike IgG, receptor-binding domain (RBD) IgG, RBD IgG + IgM + IgA, and nucleocapsid IgG of SARS-CoV-2 were measured by a non-virus ELISA kit. Multiple statistical analyses were carried out to identify factors that influence humoral immunity post-vaccination. RESULTS: The two-dosage vaccination could induce NA in more than 90 % of recipients. The NA has the strongest correlation with anti-RBD IgG. Age is the most important independent index that affects the NA level, while basophil count, creatine kinase-MB, mean corpuscular hemoglobin, the ratio of albumin to urine creatinine, and thyroglobulin antibody have relatively minor contributions. Indices that affect the NA level were different between males and females. Antibodies targeting other epitopes of SARS-CoV-2 were detected in recipients without anti-RBD. CONCLUSIONS: The factors identified in association with the NA level post-vaccination may help to evaluate the protective effect, risk of re-infection, the severity of symptoms, and prognosis for vaccine recipients in clinical.
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COVID-19 , Immunité humorale , Femelle , Mâle , Humains , SARS-CoV-2 , COVID-19/prévention et contrôle , Vaccination , Anticorps neutralisants , Vaccins contre la COVID-19 , Immunoglobuline G , Anticorps antivirauxRÉSUMÉ
INTRODUCTION: Many clinical studies reported the coexistence of Alzheimer's disease (AD) and multiple sclerosis (MS), but the common molecular signature between AD and MS remains elusive. The purpose of our study was to explore the genetic linkage between AD and MS through bioinformatic analysis, providing new insights into the shared signatures and possible pathogenesis of two diseases. METHODS: The common differentially expressed genes (DEGs) were determined between AD and MS from datasets obtained from Gene Expression Omnibus (GEO) database. Further, functional and pathway enrichment analysis, protein-protein interaction network construction, and identification of hub genes were carried out. The expression level of hub genes was validated in two other external AD and MS datasets. Transcription factor (TF)-gene interactions and gene-miRNA interactions were performed in NetworkAnalyst. Finally, receiver operating characteristic (ROC) curve analysis was applied to evaluate the predictive value of hub genes. RESULTS: A total of 75 common DEGs were identified between AD and MS. Functional and pathway enrichment analysis emphasized the importance of exocytosis and synaptic vesicle cycle, respectively. Six significant hub genes, including CCL2, CD44, GFAP, NEFM, STXBP1, and TCEAL6, were identified and verified as common hub genes shared by AD and MS. FOXC1 and hsa-mir-16-5p are the most common TF and miRNA in regulating hub genes, respectively. In the ROC curve analysis, all hub genes showed good efficiency in helping distinguish patients from controls. CONCLUSION: Our study first identified a common genetic signature between AD and MS, paving the road for investigating shared mechanism of AD and MS.
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Maladie d'Alzheimer , microARN , Sclérose en plaques , Humains , Maladie d'Alzheimer/génétique , Sclérose en plaques/génétique , microARN/génétique , Biologie informatique , Bases de données factuellesRÉSUMÉ
BACKGROUND AND AIM: FKBP1A, a gene encoding the FK506-binding protein 1A, has emerged as a significant player in cancer progression and prognosis. This study aimed to comprehensively investigate the multifaceted role of FKBP1A in cancer, focusing on its differential expression patterns, prognostic implications, genetic alterations, and associations with the tumor microenvironment. METHODS AND RESULTS: Using large-scale datasets, including GTEx, TCGA, HPA, and cBioPortal, we analyzed FKBP1A expression across normal tissues and various cancer types. Our findings revealed that FKBP1A exhibited aberrant upregulation in most human cancers, making it a potential biomarker for malignancy. Moreover, FKBP1A expression correlated with poor overall survival, disease-specific survival, disease-free interval, and progression-free interval in several cancers, indicating its prognostic significance. Genetic alteration analysis showed that FKBP1A gene amplification was prevalent, particularly in ovarian cancer. Furthermore, FKBP1A expression was associated with tumor mutational burden and microsatellite instability, highlighting its potential involvement in tumor-immune response. Notably, FKBP1A expression positively correlated with stromal and immune cell scores, suggesting its role in shaping the tumor microenvironment. Additionally, according to the functional enrichment analysis, experimental validation in lung adenocarcinoma confirmed the role of FKBP1A through the regulation of EGFR signaling by apoptosis, which is consistent with drug sensitivity analysis to some extent. CONCLUSION: In conclusion, FKBP1A exhibits differential expression in cancer, serves as a prognostic indicator, undergoes genetic alterations, and influences the tumor-immune microenvironment. These findings shed light on the multifaceted role of FKBP1A in cancer development and progression, suggesting its potential as a therapeutic target and guidance of clinical drugs selection, and provide valuable insights into patient prognosis for interventions based on pharmaceuticals.
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Adénocarcinome pulmonaire , Tumeurs du poumon , Tumeurs de l'ovaire , Humains , Femelle , Tumeurs du poumon/génétique , Pronostic , Apoptose , Microenvironnement tumoral/génétique , Protéines de liaison au tacrolimus/génétiqueRÉSUMÉ
Ever-growing evidence has revealed that group 2 innate lymphoid cells (ILC2s) exhibit pleiotropic effects in antihelminth immunity, allergy, tissue protection, and cancer. Currently, the role of ILC2s in cancer is highly controversial regarding the intricate tumor microenvironment (TME), and the tumor-promoting or antitumor immunological mechanisms of ILC2s remain largely unknown. In this study, we report that dopamine receptor 1 (DRD1) restrains ILC2 activity in the TME. DRD1 deficiency promotes ILC2 activation, which irritates eosinophil recruitment and cytotoxic CD8+ T cell expansion during ongoing malignancy. Consequently, DRD1-deficient mice exhibit delayed tumor growth and reduced tumor progression. Furthermore, fenoldopam, a selective DRD1 agonist, restrains the ILC2 response in the TME and aggravates tumor burden in mice. Taken together, our data elaborate that the DRD1 signal acts as an excitatory rheostat in regulating ILC2-dependent antitumor immunity.
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Background: Antioxidant micronutrients have a therapeutic potential for clinical treatment of obesity. NO research, however, has examined the connection between the complex level of dietary antioxidants and obesity. Materials and methods: We mainly aimed to investigate the relationship between a combination of antioxidants and obesity using the database of the national health and nutrition examination survey (NHANES). This cross-sectional study contains a survey of 41,021 people (≥18 years) in total ranging from 2005 to 2018. Multivariate logistic and weighted quantile sum (WQS) regression were performed to investigate the associations between these antioxidants, both individually and collectively, and the prevalence of obesity. The restricted cubic spline (RCS) regression was also utilized to analyze the linearity of these associations. Results: According to multivariate logistic models, we found that the levels of most antioxidants in the highest quartile were independently related to a lower prevalence of obesity, while a reverse result was observed in selenium (p for trend <0.05). The WQS index revealed that a total of the 11 antioxidants is negatively related to the prevalence of obesity and abdominal obesity (all p<0.001), and iron/vitamin C have the greatest weight in the negative associations between antioxidant complex and obesity, as well as abdominal obesity. In addition, the RCS regression showed that retinol, vitamin A, α-carotene, ß-carotene, ß-cryptoxanthin, vitamin C, iron, and copper all had a non-linear association with obesity. Threshold effect analysis demonstrated that the inflection points of retinol, vitamin A, α-carotene, ß-carotene, ß-cryptoxanthin, vitamin C, iron, and cooper were 235.57, 374.81, 58.89, 891.44, 30.70, 43,410.00, 11,240.00, and 990.00 µg/day, respectively. Conclusion: Our study found that a high level of a complex of 11 dietary antioxidants is related to a lower prevalence of obesity and abdominal obesity, among this inverse associations iron and vitamin C have the greatest weight.
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The overall survival, progress free survival, and life quality of cancer patients have improved due to the advance in minimally invasive surgery, precision radiotherapy, and various combined chemotherapy in the last decade. Furthermore, the discovery of new types of therapeutics, such as immune checkpoint inhibitors and immune cell therapies have facilitated both patients and doctors to fight with cancers. Moreover, in the context of the development in biocompatible and cell type targeting nano-carriers as well as nucleic acid-based drugs for initiating and enhancing the anti-tumor response have come to the age. The treatment paradigms utilization of nucleic acids, including short interfering RNA (siRNA), antisense oligonucleotides (ASO), and messenger RNA (mRNA), can target specific protein expression to achieve the therapeutic effects. Over ten nucleic acid therapeutics have been approved by the FDA and EMA in rare diseases and genetic diseases as well as dozens of registered clinical trails for varies cancers. Though generally less dangerous of pediatric cancers than adult cancers was observed during the past decades, yet pediatric cancers accounted for a significant proportion of child deaths which hurt those family very deeply. Therefore, it is necessary to pay more attention for improving the treatment of pediatric cancer and discovering new nucleic acid therapeutics which may help to improve the therapeutic effect and prognoses in turns to ameliorate the survival period and quality of life for children patient. In this review, we focus on the nucleic acid therapy in pediatric cancers.
Sujet(s)
Inhibiteurs de points de contrôle immunitaires , Tumeurs , Enfant , Humains , Tumeurs/traitement médicamenteux , Tumeurs/génétique , Oligonucléotides antisens/usage thérapeutique , Qualité de vie , ARN messager , Petit ARN interférent/métabolismeRÉSUMÉ
The distribution of pathogenic Legionella in the environmental soil and water of China has not been documented yet. In this study, Legionella was detected in 129 of 575 water (22.43%) and 41 of 442 soil samples (9.28%) by culture. Twelve Legionella species were identified, of which 11 were disease-associated. Of the Legionella-positive samples, 109 of 129 (84.50%) water and 29 of 41 (70.73%) soil were positive for L. pneumophila, which accounted for about 75% of Legionella isolates in both water and soil, suggesting L. pneumophila was the most frequent species. Soil showed a higher diversity of Legionella spp. as compared with water (0.6279 versus 0.4493). In contrast, serogroup (sg) 1 was more prevalent among L. pneumophila isolates from water than from soil (26.66% versus 12.21%). Moreover, many disease-associated sequence types (STs) of L. pneumophila were found in China. Intragenic recombination was acting on L. pneumophila from both water and soil. Phylogeny, population structure, and molecular evolution analyses revealed a probable existence of L. pneumophila isolates with a special genetic background that is more adaptable to soil or water sources and a small proportion of genetic difference between water and soil isolates. The detection of viable, clinically relevant Legionella demonstrates soil as another source for harboring and dissemination of pathogenic Legionella bacteria in China. Future research should assess the implication in public health with the presence of Legionella in the soil and illustrate the genetic and pathogenicity difference of Legionella between water and soil, particularly the most prevalent L. pneumophila. IMPORTANCE Pathogenic Legionella spp. is the causative agent of Legionnaires' disease (LD), and L. pneumophila is the most common one. Most studies have focused on L. pneumophila from water and clinical samples. However, the soil is another important reservoir for this bacterium, and the distribution of Legionella spp. in water and soil sources has not been compared and documented in China yet. Discovering the distribution of Legionella spp. and L. pneumophila in the two environments may help a deep understanding of the pathogenesis and molecular evolution of the bacterium. Our research systematically uncovered the distributions of Legionella spp. in different regions and sources (e.g., water and soil) of China. Moreover, phylogeny, population structure, and molecular evolution study revealed the possible existence of L. pneumophila with a special genetic background that is more adaptable to soil or water sources, and genetic difference may exist.
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Legionella pneumophila , Legionella , Maladie des légionnaires , Humains , Legionella/génétique , Maladie des légionnaires/épidémiologie , Sol , Eau , Microbiologie de l'eauRÉSUMÉ
Primary Sjögren's Disease (pSjD) is considered a B cell-mediated disease. Toll-like receptor 10 (TLR10) is highly expressed in human B cells, indicating that TLR10 probably plays a vital role in pSjD. We examined TLR10 expression in peripheral B subsets of pSjD patients and analyzed their association with disease activity. We observed that TLR10 expression in total, naïve, memory, and switched memory B cells was significantly increased in low-activity pSjD patients as compared with healthy controls and high-activity patients. TLR10 expression in the above mentioned B subsets (except naïve B) was negatively correlated with serum levels of anti-SSA antibody and BAFF, respectively. Moreover, a higher proportion of high-activity pSjD patients was observed in TLR10 low- than high-expressed patients. Our study concluded that TLR10 expression in CD19+ B and memory B was negatively correlated with pSjD disease activity, suggesting that TLR10 might take part in the progression of pSjD.
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Lymphocytes B , Syndrome de Gougerot-Sjögren , Récepteur de type Toll-10 , Antigènes CD19/métabolisme , Humains , Numération des lymphocytes , Syndrome de Gougerot-Sjögren/anatomopathologie , Récepteur de type Toll-10/métabolismeRÉSUMÉ
Lung cancer is one of the most common and mortal malignancies, usually with a poor prognosis in its advanced or recurrent stages. Recently, immune checkpoint inhibitors (ICIs) immunotherapy has revolutionized the treatment of human cancers including lung adenocarcinoma (LUAD), and significantly improved patients' prognoses. However, the prognostic and predictive outcomes differ because of tumor heterogeneity. Here, we present an effective method, GDPLichi (Genes of DNA damage repair to predict LUAD immune checkpoint inhibitors response), as the signature to predict the LUAD patient's response to the ICIs. GDPLichi utilized only 7 maker genes from 8 DDR pathways to construct the predictive model and classified LUAD patients into two subgroups: low- and high-risk groups. The high-risk group was featured by worse prognosis and decreased B cells, CD8+ T cells, CD8+ central memory T cells, hematopoietic stem cells (HSC), myeloid dendritic cells (MDC), and immune scores as compared to the low-risk group. However, our research also suggests that the high-risk group was more sensitive to ICIs, which might be explained by increased TMB, neoantigen, immune checkpoint molecules, and immune suppression genes' expression, but lower TIDE score as compared to the low-risk group. This conclusion was verified in three other LUAD cohort datasets (GSE30219, GSE31210, GSE50081).
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Effector proteins translocated by the Dot/Icm type IV secretion system determine the virulence of Legionella pneumophila (L. pneumophila). Among these effectors, members of the SidE family (SidEs) regulate several cellular processes through a unique phosphoribosyl ubiquitination mechanism mediated by another effector, SidJ. Host-cell calmodulin (CaM) activates SidJ to glutamylate the SidEs of ubiquitin (Ub) ligases and to make a balanced Ub ligase activity. Given the central role of SidJ in this regulatory process, studying the nature of evolution of sidJ is important to understand the virulence of L. pneumophila and the interaction between the bacteria and its hosts. By studying sidJ from a large number of L. pneumophila strains and using various molecular evolution algorithms, we demonstrated that intragenic recombination drove the evolution of sidJ and contributed to sidJ diversification. Additionally, we showed that four codons of sidJ which are located in the N-terminal (NTD) (codons 58 and 200) and C-terminal (CTD) (codons 868 and 869) domains, but not in the kinase domain (KD) had been subjected to strong positive selection pressure, and variable mutation profiles of these codons were identified. Protein structural modeling of SidJ provided possible explanations for these mutations. Codons 868 and 869 mutations might engage in regulating the interactions of SidJ with CaM through hydrogen bonds and affect the CaM docking to SidJ. Mutation in codon 58 of SidJ might affect the distribution of main-chain atoms that are associated with the interaction with CaM. In contrast, mutations in codon 200 might influence the α-helix stability in the NTD. These mutations might be important to balance Ub ligase activity for different L. pneumophila hosts. This study first reported that intragenic recombination and positive Darwinian selection both shaped the genetic plasticity of sidJ, contributing to a deeper understanding of the adaptive mechanisms of this intracellular bacterium to different hosts.
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Cell-penetrating peptides (CPPs), as non-viral gene delivery vectors, are considered with lower immunogenic response, and safer and higher gene capacity than viral systems. In our previous study, a CPP peptide called RALA (arginine rich) presented desirable transfection efficacy and owns a potential clinic use. It is believed that histidine could enhance the endosome escaping ability of CPPs, yet RALA peptide contains only one histidine in each chain. In order to develop novel superior CPPs, by using RALA as a model, we designed a series of peptides named HALA (increased histidine ratio). Both plasmid DNA (pDNA) and siRNA transfection results on three cell lines revealed that the transfection efficacy is better when histidine replacements were on the C-terminal instead of on the N-terminal, and two histidine replacements are superior to three. By investigating the mechanism of endocytosis of the pDNA nanocomplexes, we discovered that there were multiple pathways that led to the process and caveolae played the main role. During the screening, we discovered a novel peptide-HALA2 of high cellular transfection efficacy, which may act as an exciting gene delivery vector for gene therapy. Our findings also bring new insights on the development of novel robust CPPs.
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Elderly with comorbidities have shown a higher rate of fatal outcomes when suffering coronavirus disease 2019 (COVID-19). However, a delineation of clinical significances of hematologic indices and underlying comorbidities in the progression and outcome of COVID-19 remains undefined. Six hundred two COVID-19 patients with established clinical outcomes (discharged or deceased) from Hankou Hospital of Wuhan, China between January 14, 2020 and February 29, 2020 were retrospectively analyzed. Of the 602 patients with COVID-19, 539 were discharged and 63 died in the hospital. The deceased group showed higher leukocyte and neutrophil counts but lower lymphocyte and platelet counts. Longer activated partial thromboplastin time (APTT) and prothrombin time (PT), as well as higher D-dimer and C-reactive protein levels, were found in non-survivors. Our observations suggest that these parameters could serve as potential predictors for the fatal outcome and in the discharged group. A higher neutrophil count and D-dimer level but lower lymphocyte were associated with a longer duration of hospitalization. A multivariable Cox regression analysis showed that higher neutrophil count, prolonged PT, and low lymphocyte count were risk factors for patients with COVID-19. Also, we found an association of lower lymphocyte count and higher C-reactive protein levels with the elderly group and those with cardiovascular-related comorbidities. The significantly different hematologic profiles between survivors and non-survivors support that distinct hematologic signatures in COVID-19 patients will dictate different outcomes as a prognostic marker for recovery or fatality. Lymphopenia and aggressive inflammatory response might be major causes for fatal outcomes in the elderly male and especially those with cardiovascular-related comorbidities.
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Thrombopoietin (TPO) is a growth factor for the megakaryocytic/platelet lineage. In this study, we investigated the expression of TPO and its receptor, c-Mpl, in the human central nervous system (CNS) and their roles after a neural insult. Our results demonstrate that both TPO and c-Mpl are expressed in the neurons of the human CNS. TPO was also detected in human cerebrospinal fluid. TPO was found to be neuroprotective in hypoxic-ischemic neonatal rat brain models. In these rat models, treatment with TPO reduced brain damage and improved sensorimotor functions. In addition, TPO promoted C17.2 cell proliferation through activation of the PI3K/Akt signaling pathway. Via the Bcl-2/BAX signaling pathway, TPO exerted an antiapoptotic effect by suppressing mitochondrial membrane potentials. Taken together, our results indicate that TPO is neuroprotective in the CNS.
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Système nerveux central/métabolisme , Régulation de l'expression des gènes , Neurones/métabolisme , Récepteurs à la thrombopoïétine/génétique , Thrombopoïétine/génétique , Animaux , Apoptose , Différenciation cellulaire , Lignée cellulaire , Prolifération cellulaire , Système nerveux central/cytologie , Humains , Modèles animaux , Neurones/cytologie , Rats , Récepteurs à la thrombopoïétine/biosynthèse , Transduction du signal , Thrombopoïétine/biosynthèseRÉSUMÉ
Preterm birth (PTB) is a leading cause of neonatal death worldwide. Intrauterine and systemic infection and inflammation cause 30-40% of spontaneous preterm labor (PTL), which precedes PTB. Although antibody production is a major immune defense mechanism against infection, and B cell dysfunction has been implicated in pregnancy complications associated with PTL, the functions of B cells in pregnancy are not well known. We found that choriodecidua of women undergoing spontaneous PTL harbored functionally altered B cell populations. B cell-deficient mice were markedly more susceptible than wild-type (WT) mice to PTL after inflammation, but B cells conferred interleukin (IL)-10-independent protection against PTL. B cell deficiency in mice resulted in a lower uterine level of active progesterone-induced blocking factor 1 (PIBF1), and therapeutic administration of PIBF1 mitigated PTL and uterine inflammation in B cell-deficient mice. B cells are a significant producer of PIBF1 in human choriodecidua and mouse uterus in late gestation. PIBF1 expression by B cells is induced by the mucosal alarmin IL-33 (ref. 9). Human PTL was associated with diminished expression of the α-chain of IL-33 receptor on choriodecidual B cells and a lower level of active PIBF1 in late gestation choriodecidua. These results define a vital regulatory cascade involving IL-33, decidual B cells and PIBF1 in safeguarding term pregnancy and suggest new therapeutic approaches based on IL-33 and PIBF1 to prevent human PTL.
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Lymphocytes B/métabolisme , Caduques/métabolisme , Interleukine-33/métabolisme , Travail obstétrical prématuré/métabolisme , Protéines de la grossesse/métabolisme , Adulte , Animaux , Lymphocytes B/immunologie , Technique de Western , Caduques/cytologie , Caduques/immunologie , Modèles animaux de maladie humaine , Test ELISA , Femelle , Cytométrie en flux , Technique d'immunofluorescence , Humains , Immunohistochimie , Protéine-1 analogue au récepteur de l'interleukin-1/immunologie , Protéine-1 analogue au récepteur de l'interleukin-1/métabolisme , Interleukine-33/immunologie , Souris , Travail obstétrical prématuré/immunologie , Grossesse , Protéines de la grossesse/immunologie , Jeune adulteRÉSUMÉ
Epithelial ovarian carcinomas (EOC) cause more mortality than any other cancer of the female reproductive system. New therapeutic approaches to reduce EOC mortality have been largely unsuccessful due to the poor understanding of the mechanisms underlying EOC proliferation and metastasis. Progress in EOC treatment is further hampered by a lack of reliable prognostic biomarkers for early risk assessment. In this study, we identify that Migration-Inducting Gene 7 (MIG-7) is specifically induced in human EOC tissues but not normal ovaries or ovarian cyst. Ovarian MIG-7 expression strongly correlated with EOC progression. Elevated MIG-7 level at the time of primary cytoreductive surgery was a strong and independent predictor of poor survival of EOC patients. Cell and murine xenograft models showed that MIG-7 was required for EOC proliferation and invasion, and MIG-7 enhanced EOC-associated angiogenesis by promoting the expression of vascular endothelial growth factor. Inhibiting MIG-7 by RNA interference in grafted EOC cells retarded tumor growth, angiogenesis and improved host survival, and suppressing MIG-7 expression with a small molecule inhibitor D-39 identified from the medicinal plant Liriope muscari mitigated EOC growth and invasion and specifically abrogated the expression of vascular endothelial growth factor. Our data not only reveal a critical function of MIG-7 in EOC growth and metastasis and support MIG-7 as an independent prognostic biomarker for EOC, but also demonstrate that therapeutic targeting of MIG-7 is likely beneficial in the treatment of EOC.
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Protéines tumorales/biosynthèse , Tumeurs épithéliales épidermoïdes et glandulaires/métabolisme , Tumeurs de l'ovaire/métabolisme , Animaux , Carcinogenèse , Carcinome épithélial de l'ovaire , Lignée cellulaire tumorale , Prolifération cellulaire/physiologie , Études de cohortes , Femelle , Hétérogreffes , Humains , Souris , Souris de lignée C57BL , Souris nude , Adulte d'âge moyen , Métastase tumorale , Protéines tumorales/antagonistes et inhibiteurs , Protéines tumorales/génétique , Tumeurs épithéliales épidermoïdes et glandulaires/vascularisation , Tumeurs épithéliales épidermoïdes et glandulaires/génétique , Tumeurs épithéliales épidermoïdes et glandulaires/anatomopathologie , Néovascularisation pathologique/génétique , Néovascularisation pathologique/métabolisme , Néovascularisation pathologique/anatomopathologie , Tumeurs de l'ovaire/vascularisation , Tumeurs de l'ovaire/génétique , Tumeurs de l'ovaire/anatomopathologie , Pronostic , TransfectionRÉSUMÉ
Early diagnosis of intraperitoneal metastasis is a pivot for survival of patients with serous epithelial ovarian cancers (SEOC). However, to date, there is lack of efficient molecular biomarker for early metastasis of SEOC. Here, we found that the expression of chloride intracellular channel 1 (CLIC1) is highly correlative with intraperitoneal metastasis. There is very low expression of CLIC1 in normal ovaries (NO), benign ovarian tumor (BOT), and primary ovarian cancer without metastasis (POCNM); but its expression is remarkably high in primary ovarian cancer with metastasis (POCM) omentum and peritoneal metastasis. Furthermore, for clinic prediction of intraperitoneal metastasis of SEOC, the sensitivity and specificity of CLIC1 overexpression were 97.4 and 88.1 %, respectively. Collectively, CLIC1 may be a potential sensitive and specific molecular biomarker for early diagnose for SEOC metastasis.